Inflamed lung-targeting nanoparticles hijack activated platelets to alleviate lung injury in sepsis

Anti-inflammatory therapy is often considered as an effective way to treat sepsis, but it only relives systemic inflammation without protecting the damaged vital organs. In our present study, we found that, lung is the most vulnerable organ compared to other vital organs in the progression of sepsis, characterized by excessively inflammatory response and activated platelet accumulation. Herein, an activated platelet-targted nanoparticle (P-TPNP-pD) was designed to facilitate drug delivery to sepsis-damaged lungs. Because of the high expression of P-selectin on activated platelets, P-TPNP-pD, modified with a P-selectin-targeting peptide (PTP), could target activated platelets and significantly accumulate in sepsis-damaged lungs via effective P-selectin-PTP binding. Meanwhile, due to the low pH of inflammation sites in sepsis-damaged lungs, nanoparticles with polydopamine (pD) modification could release anti-inflammatory drugs (Piceatannol, PIC) in a pH-responsive manner. However, the anti-inflammatory treatment was insufficient to alleviate lung injury in sepsis. Aggregation of activated platelets in the lungs induced by sepsis often leads to the formation of thrombosis, resulting in pulmonary dysfunction. Therefore, we further co-loaded anti-thrombotic drugs (Ticagrelor, TIC) into those nanoparticles. The dual anti-inflammatory/anti-thrombotic therapy could profoundly achieve lung protection in a sepsis mouse model with less infiltration of neutrophils and platelets, and reduce the risk of crosstalk between neutrophils and platelets simultaneously. This work provided proof-of-concept strategy to relive systemic inflammation and protect the vital organs of lung from inflammation and thrombosis in the progression of sepsis.